dc.date.accessioned | 2020-05-27T19:26:07Z | |
dc.date.available | 2020-05-27T19:26:07Z | |
dc.date.created | 2020-01-29T12:58:10Z | |
dc.date.issued | 2020 | |
dc.identifier.citation | Kamiński, Krzysztof Esguerra, Camila V. Gawel, Kinga Aurelia . N-Benzyl-(2,5-dioxopyrrolidin-1-yl)propanamide (AS-1) with Hybrid Structure as a Candidate for a Broad-Spectrum Antiepileptic Drug. Neurotherapeutics. 2019 | |
dc.identifier.uri | http://hdl.handle.net/10852/76356 | |
dc.description.abstract | In our recent studies, we identified compound N-benzyl-2-(2,5-dioxopyrrolidin-1-yl)propanamide (AS-1) as a broad-spectrum hybrid anticonvulsant which showed potent protection across the most important animal acute seizure models such as the maximal electroshock (MES) test, the subcutaneous pentylenetetrazole (s.c. PTZ) test, and the 6-Hz (32 mA) test in mice. Therefore, AS-1 may be recognized as a candidate for new anticonvulsant effective in different types of human epilepsy with a favorable safety margin profile determined in the rotarod test in mice. In the aim of further pharmacological evaluation of AS-1, in the current study, we examined its activity in the 6-Hz (44 mA) test, which is known as the model of drug-resistant epilepsy. Furthermore, we determined also the antiseizure activity in the kindling model of epilepsy induced by repeated injection of pentylenetetrazole (PTZ) in mice. As a result, AS-1 revealed relatively potent protection in the 6-Hz (44 mA) test, as well as delayed the progression of kindling induced by repeated injection of PTZ in mice at doses of 15 mg/kg, 30 mg/kg, and 60 mg/kg. Importantly, the isobolographic analysis showed that a combination of AS-1 and valproic acid (VPA) at the fixed ratio of 1:1 displayed a supra-additive (synergistic) interaction against PTZ-induced seizures in mice. Thus, AS-1 may be potentially used in an add-on therapy with VPA. Moreover, incubation of zebrafish larvae with AS-1 substantially decreased the number, cumulative but not the mean duration of epileptiform-like events in electroencephalographic assay. Finally, the in vitro ADME-Tox studies revealed that AS-1 is characterized by a very good permeability in the parallel artificial membrane permeability assay test, excellent metabolic stability on human liver microsomes (HLMs), no significant influence on CYP3A4/CYP2D6 activity, and moderate inhibition of CYP2C9 in a concentration of 10 μM, as well as no hepatotoxic properties in HepG2 cells (concentration of 10 μM). | en_US |
dc.language | EN | |
dc.rights | Attribution 4.0 International | |
dc.rights.uri | https://creativecommons.org/licenses/by/4.0/ | |
dc.title | N-Benzyl-(2,5-dioxopyrrolidin-1-yl)propanamide (AS-1) with Hybrid Structure as a Candidate for a Broad-Spectrum Antiepileptic Drug | en_US |
dc.type | Journal article | en_US |
dc.creator.author | Kamiński, Krzysztof | |
dc.creator.author | Esguerra, Camila V. | |
dc.creator.author | Gawel, Kinga Aurelia | |
cristin.unitcode | 185,57,0,0 | |
cristin.unitname | Norsk Senter for Molekylærmedisin | |
cristin.ispublished | true | |
cristin.fulltext | original | |
dc.identifier.cristin | 1785216 | |
dc.identifier.bibliographiccitation | info:ofi/fmt:kev:mtx:ctx&ctx_ver=Z39.88-2004&rft_val_fmt=info:ofi/fmt:kev:mtx:journal&rft.jtitle=Neurotherapeutics&rft.volume=&rft.spage=&rft.date=2019 | |
dc.identifier.jtitle | Neurotherapeutics | |
dc.identifier.volume | 17 | |
dc.identifier.issue | 1 | |
dc.identifier.startpage | 309 | |
dc.identifier.endpage | 328 | |
dc.identifier.pagecount | 20 | |
dc.identifier.doi | https://doi.org/10.1007/s13311-019-00773-w | |
dc.identifier.urn | URN:NBN:no-79424 | |
dc.type.document | Tidsskriftartikkel | en_US |
dc.type.peerreviewed | Peer reviewed | |
dc.source.issn | 1933-7213 | |
dc.identifier.fulltext | Fulltext https://www.duo.uio.no/bitstream/handle/10852/76356/1/10.1007_s13311-019-00773-w.pdf | |
dc.type.version | PublishedVersion | |
dc.relation.project | NFR/187615 | |